Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
1999-07-14
2001-10-09
Bansal, Geetha P. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S136100, C424S155100, C424S183100, C424S178100, C424S194100, C424S809000, C530S350000, C530S391700, C530S387300, C530S387700, C530S389700, C514S002600, C514S04400A, C436S819000
Reexamination Certificate
active
06299876
ABSTRACT:
This invention relates to potentially cytotoxic agents which may be targeted to selected cells, and is particularly concerned with the action of agents used in the treatment of cancer.
Most forms of cancer tend to disseminate in the body at an early stage and the ultimate aim of cancer therapy is to achieve elimination of cancers, preferably without incurring serious toxic effects on host systems. Combinations of cytotoxic agents have proved curative in a small range of relatively uncommon cancers, but single agents and combinations of them have failed to achieve major therapeutic benefits in most patients with the common cancers of lung, breast, colon, rectum, pancreas, prostate etc.
Cytotoxic agents can only be given by intermittent dose schedules because of their effects on normal tissues in which cell renewal is active such as haemopoietic tissues and epithelia of the alimentary tract. The rest period between treatments which is necessary to allow recovery of these normal tissues from the effects of the cytotoxic substances tends to be of much greater duration than the period of administration of the cytotoxic agents.
Substances involved in cell division are the commonest targets for cytotoxic agents and amongst these are substances involved in the synthesis of nucleotides, the basic components of DNA and RNA. The enzymes ribonucleotide reductase, dihydrofolate reductase and thymidine synthetase are typical targets. The enzyme dihydrofolate reductase acts on a dietary factor, folic acid, to produce the active co-enzyme 5,10-methenyltetrahydrofolate. The co-enzyme is required for one carbon transfer in various syntheses including that of pyrimidines required for DNA synthesis. The widely used drug methotrexate (2,4-diamino-N
10
-methylpteroylglutamic acid) acts by binding strongly to dihydrofolate reductase preventing regeneration of active tetrahydrofolate and thus interrupting DNA synthesis and leading to death of cells entering S phase of the cell cycle in which DNA is duplicated. Methotrexate is generally available, for example from Cyanamid Inc.
The drug trimetrexate (NSC 352122; 2,4-diamino-5-methyl-6-[3,4,5-trimethoxyanilino (methyl]quinazoline) also acts by binding to dihydrofolate reductase but whereas methotrexate enters cells via the folate receptors, trimetrexate enters by alternative mechanism(s). The synthesis of trimetrexate is disclosed by Baker (1967) in
Design of site-directed irreversible enzyme inhibitors
, Wiley, New York, and by Elslager et al (1974)
Lectures in heterocyclic chemistry
, Vol. 2, pp 97/5-133 (Castle & Townsend, ed), Hetero Corp, Oren, Utah. Trimetrexate is generally available from US Biosciences, One Tower Bridge, 100 Front Street, Suite 400, West Conshohocken, Pa. 19428, USA.
Methotrexate resembles natural folates in having a terminal glutamic acid moiety which can be cleaved by carboxypeptidase G2, whereas trimetrexate is not susceptible to the action of this enzyme (Bagshawe (1985)
Clinical Radiol.
36, 545-551). We have previously reported that the action of trimetrexate on colonic cancer cells in vitro can be enhanced by the addition to the culture medium of a folate degrading enzyme carboxypeptidase G2 (Searle et al (1990)
Biochemical Pharmacol.
39, 1787-1791. We have also shown that this enzyme retains activity when conjugated to antibodies or antibody fragments (Searle et al (1988)
Bact. J. Cancer
53, 377-384).
The biological effect of both methotrexate and trimetrexate can be reversed by administering an end product of the reaction they block, or by a more readily available analogue known as folinic acid [5-formyl tetrahydrofolic acid]. Folinic acid is widely available, for example as Leucovorin from Cyanamid Inc, but also from Wellcome Inc, and Farmitalia. If folinic acid is given in sufficient dosage concurrently with methotrexate or trimetrexate their actions are blocked. It has been found useful in the treatment of some cancers to use folinic acid in conjunction with methotrexate in carefully timed and dose controlled sequences. The methotrexate-folinic acid combination can improve the therapeutic ratio compared with methotrexate alone for certain cancers and is commonly known as ‘rescue’ therapy. It appears to depend on the ability of folinic acid to rescue normal clonogenic cells more readily than some cancer cells. One example is the successful use of methotrexate and folinic acid in the treatment of some trophoblastic tumours (Bagshawe et al (1989)
Brit. J. Ob. & Gynaecol.
). However this approach has proved useful in only a limited range of cancers and it seems likely that the time x concentration of folinic acid which is necessary to protect normal cells also protects some cancer cells from the action of the anti-folate.
Moreover the use of folinic acid in this way still necessitates intermittent administration of the methotrexate (MTX), whereas it would be advantageous to give the MTX more continuously over a prolonged period since it has been shown that the duration of action of anti-folates determines the degree of cytotoxicity achieved. Similar considerations apply to other cytotoxic drugs.
One aspect of the present invention provides a compound comprising a target cell-specific portion and an inactivating portion capable of converting a substance which, in its native state, is able to inhibit the effect of a cytotoxic agent into a substance which has less effect against said cytotoxic agent.
The inactivating portion may be directly or indirectly inactivating.
By “directly inactivating” we mean that the portion itself is able to inactivate the said substance, for example by binding to it or by converting it into an inactive form.
By “indirectly inactivating” we mean that delivery of the portion to the target cell results in inactivation of the cytotoxic agent. For example, the portion may be a nucleic acid, either DNA or RNA, that encodes a polypeptide that is able to inactivate the said substance, for example by binding to it or by converting it into an inactive form.
The said polypeptide may be expressed intracellularly, may be expressed on the cell surface, or may be secreted from the cell. By the term “polypeptide” we include proteins and glycoproteins.
Preferably, the inactivating portion is an enzymatically active portion.
Substances which “inhibit” the effect of a cytotoxic agent are those which diminish to a useful extent the ability of the cytotoxic agent to destroy target cells. Preferably, the said ability is reduced to substantially zero. Similarly, the inactivating portion will reduce such inhibition to a useful extent and will preferably reduce it to substantially zero.
The entity which is recognised by the target cell-specific portion may be any suitable entity which is expressed by tumour cells, virally-infected cells, pathogenic microorganisms, cells introduced as part of gene therapy or normal cells of the body which one wishes to destroy for a particular reason. The entity should preferably be present or accessible to the targeting portion in significantly greater concentrations in or on cells which are to be destroyed than in any normal tissues of the host that cannot be functionally replaced by other therapeutic means. Use of a target expressed by a cancer cell would not be precluded, for example, by its equal or greater expression on an endocrine tissue or organ. In a life-saving situation the organ could be sacrificed provided its function was either not essential to life, for example in the case of the testes, or could be supplied by hormone replacement therapy. Such considerations would apply, for instance, to the thyroid gland, parathyroids, adrenal cortex and ovaries.
The entity which is recognised will often be an antigen. Tumour-associated antigens, when they are expressed on the cell membrane or secreted into tumour extra-cellular fluid, lend themselves to the role of targets for antibodies.
The term “tumour” is to be understood as referring to all forms of neoplastic cell growth, including tumours of the lung, liver, blood cells (leukaemias), skin, pancrea
Bansal Geetha P.
Enzacta R & D Limited
Nixon & Peabody LLP
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